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      Excessive Extracellular ATP Desensitizes P2Y2 and P2X4 ATP Receptors Provoking Surfactant Impairment Ending in Ventilation-Induced Lung Injury

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          Abstract

          Stretching the alveolar epithelial type I (AT I) cells controls the intercellular signaling for the exocytosis of surfactant by the AT II cells through the extracellular release of adenosine triphosphate (ATP) (purinergic signaling). Extracellular ATP is cleared by extracellular ATPases, maintaining its homeostasis and enabling the lung to adapt the exocytosis of surfactant to the demand. Vigorous deformation of the AT I cells by high mechanical power ventilation causes a massive release of extracellular ATP beyond the clearance capacity of the extracellular ATPases. When extracellular ATP reaches levels >100 μM, the ATP receptors of the AT II cells become desensitized and surfactant impairment is initiated. The resulting alteration in viscoelastic properties and in alveolar opening and collapse time-constants leads to alveolar collapse and the redistribution of inspired air from the alveoli to the alveolar ducts, which become pathologically dilated. The collapsed alveoli connected to these dilated alveolar ducts are subject to a massive strain, exacerbating the ATP release. After reaching concentrations >300 μM extracellular ATP acts as a danger-associated molecular pattern, causing capillary leakage, alveolar space edema, and further deactivation of surfactant by serum proteins. Decreasing the tidal volume to 6 mL/kg or less at this stage cannot prevent further lung injury.

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          Nucleotide signalling during inflammation.

          Inflammatory conditions are associated with the extracellular release of nucleotides, particularly ATP. In the extracellular compartment, ATP predominantly functions as a signalling molecule through the activation of purinergic P2 receptors. Metabotropic P2Y receptors are G-protein-coupled, whereas ionotropic P2X receptors are ATP-gated ion channels. Here we discuss how signalling events through P2 receptors alter the outcomes of inflammatory or infectious diseases. Recent studies implicate a role for P2X/P2Y signalling in mounting appropriate inflammatory responses critical for host defence against invading pathogens or tumours. Conversely, P2X/P2Y signalling can promote chronic inflammation during ischaemia and reperfusion injury, inflammatory bowel disease or acute and chronic diseases of the lungs. Although nucleotide signalling has been used clinically in patients before, research indicates an expanding field of opportunities for specifically targeting individual P2 receptors for the treatment of inflammatory or infectious diseases.
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            Purinergic regulation of the immune system.

            Cellular stress or apoptosis triggers the release of ATP, ADP and other nucleotides into the extracellular space. Extracellular nucleotides function as autocrine and paracrine signalling molecules by activating cell-surface P2 purinergic receptors that elicit pro-inflammatory immune responses. Over time, extracellular nucleotides are metabolized to adenosine, leading to reduced P2 signalling and increased signalling through anti-inflammatory adenosine (P1 purinergic) receptors. Here, we review how local purinergic signalling changes over time during tissue responses to injury or disease, and we discuss the potential of targeting purinergic signalling pathways for the immunotherapeutic treatment of ischaemia, organ transplantation, autoimmunity or cancer.
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              Mammalian G proteins and their cell type specific functions.

              Heterotrimeric G proteins are key players in transmembrane signaling by coupling a huge variety of receptors to channel proteins, enzymes, and other effector molecules. Multiple subforms of G proteins together with receptors, effectors, and various regulatory proteins represent the components of a highly versatile signal transduction system. G protein-mediated signaling is employed by virtually all cells in the mammalian organism and is centrally involved in diverse physiological functions such as perception of sensory information, modulation of synaptic transmission, hormone release and actions, regulation of cell contraction and migration, or cell growth and differentiation. In this review, some of the functions of heterotrimeric G proteins in defined cells and tissues are described.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                13 April 2018
                April 2018
                : 19
                : 4
                : 1185
                Affiliations
                [1 ]Mobile Intensive Care Unit Zuid-West Nederland, 3062 NW Rotterdam, The Netherlands; jmeeder@ 123456chello.nl
                [2 ]Department of Surgery, Erasmus MC, Erasmus Universiteit Rotterdam, 3015 CE Rotterdam, The Netherlands
                [3 ]Department of Surgery, Upstate Medical University, Syracuse, NY 13210, USA; satalinj@ 123456upstate.edu (J.S.); kolliscm@ 123456upstate.edu (M.K.-S.); niemang@ 123456upstate.edu (G.F.N.)
                [4 ]Adult Intensive Care Unit, Erasmus MC, Erasmus Universiteit Rotterdam, 3015 CE Rotterdam, The Netherlands; p.vanderzee@ 123456erasmusmc.nl (P.v.d.Z.); p.somhorst@ 123456erasmusmc.nl (P.S.); c.denuil@ 123456erasmusmc.nl (C.d.U.)
                [5 ]Department of Anesthesiology, Universitair Medisch Centrum Utrecht, 3584 CX Utrecht, The Netherlands; p.blankman@ 123456umcutrecht.nl
                [6 ]Department of Anesthesiology, Shimane University, Izumo, Shimane Prefecture 693-0021, Japan; atsukos@ 123456med.shimane-u.ac.jp
                [7 ]Department of Cardiology, Erasmus MC, Erasmus Universiteit Rotterdam, 3062 PA Rotterdam, The Netherlands
                [8 ]Department of Anesthesiology and Critical Care Medicine, Showa University, School of Medicine, Tokyo 142-8666, Japan; trkotani@ 123456med.showa-u.ac.jp
                Author notes
                [* ]Correspondence: djohasan@ 123456gmail.com ; Tel.: +31-622804415
                Author information
                https://orcid.org/0000-0002-5577-6848
                https://orcid.org/0000-0003-1383-3637
                https://orcid.org/0000-0001-9504-0061
                Article
                ijms-19-01185
                10.3390/ijms19041185
                5979391
                29652806
                9fa4db48-9767-41d9-8552-ca57589fbf23
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 05 March 2018
                : 10 April 2018
                Categories
                Review

                Molecular biology
                extracellular atp,purinergic signaling,p2x receptors,p2y receptors,surfactant dysfunction,ventilation-induced lung injury,innate immunity

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